The present invention relates to an improved synthesis of both enantiomers of ipsenol and ipsdienol in high optical purity and in good yields, as well as an improved method for the isoprenylation of aldehydes and novel intermediates therefor.
Bark beetles of the Ips genus are major pests in conifer forests and are responsible for mass attacks in pine forests. These beetles signal aggregation and colonization by phermonal communication which involves three terpene alcohols, ipsenol (2-methyl-6-methylene-2,7-octadien-4-ol), ipsdienol (2-methyl-6-methylene-7-octen-4-ol) and cis-verbenol. The absolute configurations of the terpene alcohols identified as the principal components of these attractants have been determined as (S)-(-)-ipsenol, (S)-(+)-ipsdienol and (1S, 4S, 5S)-cis-verbenol. Their antipodes are biologically inactive. See for example J. Vite et al. Nature, Vol. 272, pp. 817-818 (27 Apr. 25, 1978); R. Silverstein et al., Science, Vol. 54, pp 509-510 (28 Oct. 1966).
The five-spined engraver beetle, Ips grandicollis, aggregates only in response to (S)-ipsenol, both ipsenol and ipsdienol constitute aggregation pheromones of the spruce-infesting bark beetle, Ips typographus and ipsdienol is present in the population attractant of Ips sexdentatus.
Because these compounds are important as lures for attracting and trapping these pests on a large scale, various investigators have attempted to develop satisfactory processes for the production of the biologically active isomers.
Many syntheses of racemic ipsenol and ipsdienol are available in the literature. See for example, Bubnov, Yu et al., Tetrahedron Lett. 1987, 26, 2797; Silverstein, R. M. et al., Science, 1966, 154, 509; Karlsen, S. et al., Acta chem. Scan. B, 1970, 30, 664; Cazes B. et al., J. Organometal Chem. 1979, 177, 67; A. Hosomi et al., Tetrahedron Leters, 1979, 429; Y. Masaki et al., J. Chem. Soc. Perkin Trans.I, 1984, 1289; and Klusener, P. A. A. et al., J Org. Chem. 1987, 52, 5261.
Mori first synthesized both of these pheromones in optically active form and assigned their configurations. Mori's initial synthesis of ipsenol, starting from leucine, was both lengthy and cumbersome and resulted in low chemical ( about 5%) and optical yields (80%). K. Mori: Tetrahedron Lett. 1975, 2187; K. Mori: Tetrahedron 1976, 32, 1101. Later, Mori modified his procedure to obtain optically pure ipsenol (.gtoreq.99%) but the overall yield still remained low. Ipsdienol starting from (R)-malic acid gave 90% ee for the pheromone. K. Mori: Tetrahedron Lett. 1976, 1609; K. Mori et al., Tetrahedron 1979, 35, 933.
Additional enantioselective syntheses have since been reported. Ohloff et al. prepared ipsdienol in 91% ee (R) and 80% ee (S) from the enantiomers of verbenone via the corresponding .beta.-pinene-4-ols, G. Ohloff et al.: Helv. Chim Acta. 1977, 60, 1496. Norin prepared racemic ipsdienol via sensitized photooxidation of commercially available myrcene followed by acid catalyzed rearrangement, P. Baeckstrom et al.: Acta Chem. Scand. B. 1983, 37, 1. Oxidation of the tertiary alcohol obtained from photooxidation to myrcenone, followed by asymmetric reduction of the carbonyl moiety using Noyori's Binal-H (J. Am. Chem. Soc., 1984, 106, 6709, 6717) provided both enantiomers of ipsdienol in 63% ee. Modified Binal-H provided ipsdienol of even lower optical purity. P. Baeckstrom et al, supra. H. Yamamoto's condensation of isovaleraldehyde with the tartrate ester of allenyl boronic acid provided the corresponding homopropargylic alcohol which was further elaborated to the 2-brominated alcohol. Protection of the alcohol as the tetrahydropyranyl ether followed by treatment with the vinyl Grignard reagent and deprotection furnished (-) ipsenol in .gtoreq.99% ee. See N. Ikeda et al., J. Am. Chem. Soc. 1986, 108, 143.
Despite the substantial efforts of numerous investigators, prior art procedures are generally expensive, multistepped processes that produce the desired opticals in low yields and/or low optical purity. The present invention provides an elegant process for producing these important pheromones in high optical purity and excellent yields compared with the prior art.